BACKGROUND: Of the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)-cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT. METHODS: We assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donor KIR genotyping and evaluated the clinical effect of donor KIR genotype and donor and recipient HLA genotypes. RESULTS: Patients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P=0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P=0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P=0.01). CONCLUSIONS: Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C-dependent manner, and donor KIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.).
BACKGROUND: Of the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)-cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT. METHODS: We assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donorKIR genotyping and evaluated the clinical effect of donorKIR genotype and donor and recipient HLA genotypes. RESULTS:Patients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P=0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P=0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P=0.01). CONCLUSIONS: Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. DonorKIR2DS1 appeared to provide protection against relapse in an HLA-C-dependent manner, and donorKIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.).
Authors: Joseph H Chewning; Charlotte N Gudme; Katharine C Hsu; Annamalai Selvakumar; Bo Dupont Journal: J Immunol Date: 2007-07-15 Impact factor: 5.422
Authors: Stephanie J Lee; John Klein; Michael Haagenson; Lee Ann Baxter-Lowe; Dennis L Confer; Mary Eapen; Marcelo Fernandez-Vina; Neal Flomenberg; Mary Horowitz; Carolyn K Hurley; Harriet Noreen; Machteld Oudshoorn; Effie Petersdorf; Michelle Setterholm; Stephen Spellman; Daniel Weisdorf; Thomas M Williams; Claudio Anasetti Journal: Blood Date: 2007-09-04 Impact factor: 22.113
Authors: Sarah Cooley; Elizabeth Trachtenberg; Tracy L Bergemann; Koy Saeteurn; John Klein; Chap T Le; Steven G E Marsh; Lisbeth A Guethlein; Peter Parham; Jeffrey S Miller; Daniel J Weisdorf Journal: Blood Date: 2008-10-22 Impact factor: 22.113
Authors: Sandeep K Tripathy; Peter A Keyel; Liping Yang; Jeanette T Pingel; Tammy P Cheng; Achim Schneeberger; Wayne M Yokoyama Journal: J Exp Med Date: 2008-07-07 Impact factor: 14.307
Authors: R Willemze; C A Rodrigues; M Labopin; G Sanz; G Michel; G Socié; B Rio; A Sirvent; M Renaud; L Madero; M Mohty; C Ferra; F Garnier; P Loiseau; J Garcia; L Lecchi; G Kögler; Y Beguin; C Navarrete; T Devos; I Ionescu; K Boudjedir; A-L Herr; E Gluckman; V Rocha Journal: Leukemia Date: 2009-01-08 Impact factor: 11.528
Authors: Mohamed L Sorror; Rainer F Storb; Brenda M Sandmaier; Richard T Maziarz; Michael A Pulsipher; Michael B Maris; Smita Bhatia; Fabiana Ostronoff; H Joachim Deeg; Karen L Syrjala; Elihu Estey; David G Maloney; Frederick R Appelbaum; Paul J Martin; Barry E Storer Journal: J Clin Oncol Date: 2014-08-25 Impact factor: 44.544
Authors: Anita J Kumar; Soyoung Kim; Michael T Hemmer; Mukta Arora; Stephen R Spellman; Joseph A Pidala; Daniel R Couriel; Amin M Alousi; Mahmoud D Aljurf; Jean-Yves Cahn; Mitchell S Cairo; Corey S Cutler; Shatha Farhan; Usama Gergis; Gregory A Hale; Shahrukh K Hashmi; Yoshihiro Inamoto; Rammurti T Kamble; Mohamed A Kharfan-Dabaja; Margaret L MacMillan; David I Marks; Hideki Nakasone; Maxim Norkin; Muna Qayed; Olle Ringden; Harry C Schouten; Kirk R Schultz; Melhem M Solh; Takanori Teshima; Alvaro Urbano-Ispizua; Leo F Verdonck; Robert Peter Gale; Betty K Hamilton; Navneet S Majhail; Alison W Loren Journal: Blood Adv Date: 2018-05-08
Authors: Wei Wang; Amy K Erbe; Mikayla Gallenberger; KyungMann Kim; Lakeesha Carmichael; Dustin Hess; Eneida A Mendonca; Yiqiang Song; Jacquelyn A Hank; Su-Chun Cheng; Sabina Signoretti; Michael Atkins; Alexander Carlson; Jonathan M Weiss; James Mier; David Panka; David F McDermott; Paul M Sondel Journal: Cancer Immunol Immunother Date: 2016-09-30 Impact factor: 6.968
Authors: Shiqiu Xiong; Andrew M Sharkey; Philippa R Kennedy; Lucy Gardner; Lydia E Farrell; Olympe Chazara; Julien Bauer; Susan E Hiby; Francesco Colucci; Ashley Moffett Journal: J Clin Invest Date: 2013-09-16 Impact factor: 14.808
Authors: Jeffrey W Leong; Julie M Chase; Rizwan Romee; Stephanie E Schneider; Ryan P Sullivan; Megan A Cooper; Todd A Fehniger Journal: Biol Blood Marrow Transplant Date: 2014-01-13 Impact factor: 5.742
Authors: Ivy T Tran; Ashley R Sandy; Alexis J Carulli; Christen Ebens; Jooho Chung; Gloria T Shan; Vedran Radojcic; Ann Friedman; Thomas Gridley; Amy Shelton; Pavan Reddy; Linda C Samuelson; Minhong Yan; Christian W Siebel; Ivan Maillard Journal: J Clin Invest Date: 2013-04 Impact factor: 14.808